Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Management of warfarin-associated bleeding or supratherapeutic INR

Russell D Hull, MBBS, MSc
David A Garcia, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


Warfarin is associated with an increased risk of bleeding, as are a variety of other anticoagulants. The effect of warfarin has great inter- and intra-individual variation based on a variety of genetic, dietary, and medication effects. This topic discusses risk factors for warfarin-associated bleeding and poor international normalized ratio (INR) control and presents an approach to the management of a patient with these complications.

The following special populations are discussed in separate topic reviews:

Intracerebral hemorrhage – (See "Reversal of anticoagulation in warfarin-associated intracerebral hemorrhage".)

Surgery/invasive procedure – (See "Perioperative management of patients receiving anticoagulants".)

Patient with a prosthetic heart valve – (See "Antithrombotic therapy for prosthetic heart valves: Indications".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Tue Jan 03 00:00:00 GMT+00:00 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. http://packageinserts.bms.com/pi/pi_coumadin.pdf (Accessed on April 13, 2015).
  2. http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088578.pdf (Accessed on April 13, 2015).
  3. Gomes T, Mamdani MM, Holbrook AM, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ 2013; 185:E121.
  4. Palareti G. Direct oral anticoagulants and bleeding risk (in comparison to vitamin K antagonists and heparins), and the treatment of bleeding. Semin Hematol 2014; 51:102.
  5. Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007; 177:347.
  6. Schelleman H, Bilker WB, Brensinger CM, et al. Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk. Am J Med 2010; 123:151.
  7. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912.
  8. Fitzmaurice DA, Blann AD, Lip GY. Bleeding risks of antithrombotic therapy. BMJ 2002; 325:828.
  9. Veeger NJ, Piersma-Wichers M, Tijssen JG, et al. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol 2005; 128:513.
  10. Odén A, Fahlén M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002; 325:1073.
  11. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105:91.
  12. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348:633.
  13. Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159:457.
  14. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897.
  15. van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002; 288:2441.
  16. Wells PS, Forgie MA, Simms M, et al. The outpatient bleeding risk index: validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med 2003; 163:917.
  17. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004; 35:2362.
  18. Douketis JD, Arneklev K, Goldhaber SZ, et al. Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, case-fatality rate, time course and sites of bleeding, and risk factors for bleeding. Arch Intern Med 2006; 166:853.
  19. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151:713.
  20. Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Anand S, Yusuf S, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007; 357:217.
  21. Ruíz-Giménez N, Suárez C, González R, et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100:26.
  22. Nieto JA, Solano R, Ruiz-Ribó MD, et al. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry. J Thromb Haemost 2010; 8:1216.
  23. Zhao HJ, Zheng ZT, Wang ZH, et al. "Triple therapy" rather than "triple threat": a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment. Chest 2011; 139:260.
  24. Hylek EM, Chang YC, Skates SJ, et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 2000; 160:1612.
  25. Veeger NJ, Piersma-Wichers M, Meijer K, Hillege HL. Minor bleeds alert for subsequent major bleeding in patients using vitamin K antagonists. Br J Haematol 2011; 153:508.
  26. Crowther MA, Ageno W, Garcia D, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med 2009; 150:293.
  27. Kucher N, Connolly S, Beckman JA, et al. International normalized ratio increase before warfarin-associated hemorrhage: brief and subtle. Arch Intern Med 2004; 164:2176.
  28. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. The European Atrial Fibrillation Trial Study Group. N Engl J Med 1995; 333:5.
  29. Torn M, van der Meer FJ, Rosendaal FR. Lowering the intensity of oral anticoagulant therapy: effects on the risk of hemorrhage and thromboembolism. Arch Intern Med 2004; 164:668.
  30. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348:423.
  31. Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb Haemost 2001; 86:569.
  32. Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs. Clin Pharmacol Ther 2001; 69:451.
  33. Penning-van Beest FJ, Geleijnse JM, van Meegen E, et al. Lifestyle and diet as risk factors for overanticoagulation. J Clin Epidemiol 2002; 55:411.
  34. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e44S.
  35. Knijff-Dutmer EA, Van der Palen J, Schut G, Van de Laar MA. The influence of cyclo-oxygenase specificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant coumarine users. QJM 2003; 96:513.
  36. Donzé J, Rodondi N, Waeber G, et al. Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study. Am J Med 2012; 125:1095.
  37. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 2011; 58:395.
  38. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093.
  39. Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011; 57:173.
  40. Olesen JB, Lip GY, Hansen PR, et al. Bleeding risk in 'real world' patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort. J Thromb Haemost 2011; 9:1460.
  41. Apostolakis S, Lane DA, Guo Y, et al. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol 2012; 60:861.
  42. Cairns JA, Connolly S, McMurtry S, et al. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011; 27:74.
  43. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37:2893.
  44. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S.
  45. Watson HG, Baglin T, Laidlaw SL, et al. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol 2001; 115:145.
  46. Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 2006; 4:1853.
  47. Garcia D, Crowther MA, Ageno W. Practical management of coagulopathy associated with warfarin. BMJ 2010; 340:c1813.
  48. Schulman S. Clinical practice. Care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003; 349:675.
  49. O'Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126:11.
  50. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008; 83:137.
  51. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e152S.
  52. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm350239.pdf (Accessed on May 08, 2015).
  53. Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002; 137:884.
  54. Lin J, Hanigan WC, Tarantino M, Wang J. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg 2003; 98:737.
  55. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015; 385:2077.
  56. Refaai MA, Goldstein JN, Lee ML, et al. Increased risk of volume overload with plasma compared with four-factor prothrombin complex concentrate for urgent vitamin K antagonist reversal. Transfusion 2015; 55:2722.
  57. Gunther KE, Conway G, Leibach L, Crowther MA. Low-dose oral vitamin K is safe and effective for outpatient management of patients with an INR>10. Thromb Res 2004; 113:205.
  58. Crowther MA, Julian J, McCarty D, et al. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet 2000; 356:1551.
  59. Weibert RT, Le DT, Kayser SR, Rapaport SI. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997; 126:959.
  60. Lubetsky A, Yonath H, Olchovsky D, et al. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 2003; 163:2469.
  61. Wilson SE, Watson HG, Crowther MA. Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review. CMAJ 2004; 170:821.
  62. Hylek EM, Regan S, Go AS, et al. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 2001; 135:393.
  63. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med 2002; 137:251.
  64. Baker P, Gleghorn A, Tripp T, et al. Reversal of asymptomatic over-anticoagulation by orally administered vitamin K. Br J Haematol 2006; 133:331.
  65. Chirputkar SK, Poole HJ, McNeil RC, et al. Reversal of asymptomatic over-anticoagulation with oral vitamin K. Br J Haematol 2006; 135:591.
  66. Bauman ME, Black K, Bauman ML, et al. Warfarin induced coagulopathy in children: assessment of a conservative approach. Arch Dis Child 2011; 96:164.
  67. Ageno W, Crowther M, Steidl L, et al. Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial. Thromb Haemost 2002; 88:48.
  68. Fondevila CG, Grosso SH, Santarelli MT, Pinto MD. Reversal of excessive oral anticoagulation with a low oral dose of vitamin K1 compared with acenocoumarine discontinuation. A prospective, randomized, open study. Blood Coagul Fibrinolysis 2001; 12:9.
  69. Ageno W, Garcia D, Silingardi M, et al. A randomized trial comparing 1 mg of oral vitamin K with no treatment in the management of warfarin-associated coagulopathy in patients with mechanical heart valves. J Am Coll Cardiol 2005; 46:732.
  70. Banet GA, Waterman AD, Milligan PE, et al. Warfarin dose reduction vs watchful waiting for mild elevations in the international normalized ratio. Chest 2003; 123:499.
  71. Laposata M, Van Cott EM, Lev MH. Case records of the Massachusetts General Hospital. Case 1-2007. A 40-year-old woman with epistaxis, hematemesis, and altered mental status. N Engl J Med 2007; 356:174.
  72. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med 2000; 36:262.
  73. Weitzel JN, Sadowski JA, Furie BC, et al. Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum: clinical and metabolic studies of three cases. Blood 1990; 76:2555.
  74. Waien SA, Hayes D Jr, Leonardo JM. Severe coagulopathy as a consequence of smoking crack cocaine laced with rodenticide. N Engl J Med 2001; 345:700.
  75. Spahr JE, Maul JS, Rodgers GM. Superwarfarin poisoning: a report of two cases and review of the literature. Am J Hematol 2007; 82:656.
  76. Schulman S, Furie B. How I treat poisoning with vitamin K antagonists. Blood 2015; 125:438.
  77. Hollinger BR, Pastoor TP. Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med 1993; 153:1925.
  78. Evans SJ, Biss TT, Wells RH, Hanley JP. Emergency warfarin reversal with prothrombin complex concentrates: UK wide study. Br J Haematol 2008; 141:268.
  79. Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 2009; 49:1171.
  80. http://www.kcentra.com/docs/Kcentra_Prescribing_Information.pdf (Accessed on May 09, 2013).
  81. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234.
  82. Joseph R, Burner J, Yates S, et al. Thromboembolic outcomes after use of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal in a real-world setting. Transfusion 2016; 56:799.
  83. Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding. Br J Haematol 2001; 115:998.
  84. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol 2002; 116:619.
  85. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6:622.
  86. Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011; 106:429.
  87. Felton D, Foley EM, Traub SJ, et al. Risk of Venous Thromboembolism After Receiving Prothrombin Complex Concentrate for Warfarin-associated Intracranial Hemorrhage. J Emerg Med 2016; 50:1.
  88. Dezee KJ, Shimeall WT, Douglas KM, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med 2006; 166:391.
  89. Nakagawa K, Hirota Y, Sawada N, et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 2010; 468:117.
  90. Li J, Brown J, Levine M. Mild head injury, anticoagulants, and risk of intracranial injury. Lancet 2001; 357:771.
  91. Brewer ES, Reznikov B, Liberman RF, et al. Incidence and predictors of intracranial hemorrhage after minor head trauma in patients taking anticoagulant and antiplatelet medication. J Trauma 2011; 70:E1.
  92. Culclasure TF, Bray VJ, Hasbargen JA. The significance of hematuria in the anticoagulated patient. Arch Intern Med 1994; 154:649.
  93. Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis 2009; 54:1121.
  94. Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 2011; 80:181.
  95. Kuramatsu JB, Gerner ST, Schellinger PD, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 2015; 313:824.
  96. Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med 2012; 172:1484.